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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Ms. Kathryn Montague, 703

- 305

- 1243

Syngenta Crop Protection, LLC

[ 4F8240 ]

EPA has received a pesticide petition ( 4F8240 ) from Syngenta Crop Protection, LLC, PO Box 18300, Greensboro, NC, 27419 request ing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346 a(d), to amend 40 CFR part 180

by establishing a tolerance for residues of

Mesotrione ( 2

- [4

- (methylsulfonyl)

- 2

- notrobenzoyl]

- 1,3

- cyclohexadione ) in or o n the raw agricultural commodities Citrus Fruit, Crop Group 10

- 10 at 0.01 parts per million (ppm)

, P ome Fruit , Crop Group 11

- 10 at 0.01 ppm , Stone Fruit, Crop Group 12

- 12 at 0.01 ppm , Tree Nuts, Crop Group 14

- 12 at 0.01 ppm, and Almond Hulls at 0.015 ppm

. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chem istry

1. Plant metabolism. The metabolism of mesotrione is adequately understood for the purpose of the proposed tolerance s, based on acceptable cranberry, corn and peanut metabolism studies. EPA has determined that, for mesotrione, the residue of concer n in plants for both enforcement and risk assessment purposes is parent mesotrione.

2. Analytical method. Syngenta has developed and validated analytical methodology for enforcement purposes. Practical and specific analytical method RAM 366/01 , utilizin g high

- performance liquid chromatography (HPLC) with tandem mass

spectrometry (MS/MS) detection, is available for detecting and measuring the level of mesotrione in or on various crop commodities. This method has been submitted to the Agency for inclusio n in the Pesticide Analytical Manual Volume II (PAM II) as a confirmatory method.

3. Magnitude of residues. Complete residue data to support the requested tolerances are submitted with this petition. The requested tolerances are adequately supported. Th e residue studies were conducted per EPA Test Guidelines 860.1000, 860.1500, and 860.1520.2

B. Toxicological Profile EPA has evaluated the available toxicity data and considered its validity , completeness, and reliability as well as the relationship of the results of the studies to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children. The nature of the toxic effects caused by m esotrione as well as the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) from the toxicity studies reviewed are discussed in the Federal Register of June 21, 2001 (66 FR 33187) (FRL

– 67877). A summary of the toxicological endpoints for mesotrione used for human risk assessment is discussed in Unit III.B of the final rule published in the Federal Register of June 21, 2001. The data was reviewed and more recently discussed in Unit III of the final rule publishe d in the Federal Register of December 18, 2009 in support of newly approved use on soybean.

1. Acute toxicity. The database for acute toxicity of mesotrione is considered to be complete. Mesotrione has low acute toxicity (toxicity category IV) via the

o ral, dermal and inhalation routes of exposure. It is a mild eye irritant (toxicity category IV), is non

- irritating dermally (toxicity category IV) and is not a dermal sensitizer.

2. Genotoxic i ty. Gene mutation (Guidelines 870.5100 & 870.5300), cytogenet ics (Guideline 870.5375) and micronucleus (Guideline 870. 5395) stud ies conducted with mesotrione have been reviewed and approved by EPA. There is no evidence of a mutagenic or cytogenetic effect in viv o or in vitro with mesotrione

.
3

. Reproductive and d evelopmental toxicity

. There is evidence of increased susceptibility of rats, mice and rabbits to in utero and/or post

- natal exposure to mesotrione

. However, there is a well characterized NOAEL that is protective of the observed effects. A reproduction s tudy in the mouse had a LOAEL of 2.1 mg/kg/day in males based on tyrosinemia and ocular discharge in offspring. This endpoint was used to establish the point of departure used in risk assessments.

4

. Subchronic toxicity. In a 90

- day dietary study in rat s with mesotrione, corneal lesions were observed in males at 0.63 mg/kg/day; the NOAEL was 0.41 mg/kg/day for males and 0.47 mg/kg/day for females . In another 90

- day dietary study in rats, corneal lesions in both sexes and decreased body weight g ain in ma les was observed at 11 mg/kg/day in males and 13 mg/kg/day in females ; t he N OAEL was 0.09 and 0.10 mg/kg/day in males and females, respectively . Ninety

- day oral studies with mesotrione in both the mouse and dog have been accepted by EPA; no effects were o bserved in males and fem ales at the highest doses tested (1212/1537 mg/kg/day [M/F] in mice and 1000 mg/kg/day [M & F] in dogs)

.

5. Chronic toxicity

. Chronic studies have been conducted with mesotrione in the rat, mouse and dog. Major adverse effects w ere ocular lesions, liver and kidney effects

, increased plasma tyrosine levels and body weight decreases. The chronic reference dose3

used for risk assessment purposes is 0.007 mg/kg/day and is protective of the effects observed

.

6. Animal metabolism. An imal metabolism studi es have shown that mesotrione is readily absorbed and alm ost totally eliminated within 72 hours following oral or intravenous admi nistration in rats and mice

. Parent compound, mesotrione, was the major compound identified in excreta. Minor metabolites identified were 4

- OH

mesotrione, 5

- OH

- mesotrione, MNBA and AMBA.

7. Metabolite toxicology

. The metabolism of mesotrione has been well characterized in standard FIFRA metabolism studies. The residue of concern in plants, livestock and drinking water is parent mesotrione.

8. Endocrine disruption

. Mesotrione does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system. Developmental toxicity studies in the rat, rabbit, and mouse, and repr oduction studies in rats and mice gave no indication that mesotrione would have any effect on endocrine function related to development and reproduction. Furthermore, histological investigations of endocrine organs (adrenals, thyroid, and pituitary) in th e long

- term studies in dog, rat, and mouse did not indicate that the endocrine system is targeted by mesotrione, even when animals were treated at maximally tolerated doses over chronic time periods. D ue to the rapid degradation of the product in the envi ronment, there is no risk that mesotrione will bioaccumulate. Based on these results and the comprehensive da tabase, mesotrione is not expected to interfere with the endocrine system in humans or wildlife

.

C. Aggregate Exposure

1. Dietary exposure. Tier II short

- term and chronic dietary exposure evaluations were completed for mesotrione using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID, version 3.16). DEEM

- FCID software incorporates food consumption data from the National Health an d Nutrition Examination Survey “What We Eat in America” (NHANES/WWEIA) dietary survey conducted in 2003

- 2008 . In addition to all currently registered uses of mesotrione (asparagus, berry Crop Group (Crop Group 13), field co rn, sweet corn, popcorn , cranberry, flax, grasses grown for seed, millet, oat, okra, rhubarb, sorghum, and sugarcane), and the pending reinstatement of aerial applications for corn and sugarcane and the pending use on herbicide (mesotrione) tolerant soybea ns (HT soybeans), this exposure assessment included proposed crop uses on citrus fruits (Crop Group 10

- 10 ), pome fruits (Crop Group 11

- 10 ), stone fruits (Crop Group 12

- 12 ) and tree nuts (Crop Group 14

- 12 ). The definition of the residue for tolerance enforc ement and risk assessment purposes for crops is parent mesotrione. The assessments utilized residue data from field trials in which mesotrione was applied at the maximum intended use rate and samples were harvested at the minimum pre

- harvest interval (PHI ) to obtain maximum residues. Percent of crop treated values were estimated based upon economic, pest, and competitive pressures for the proposed uses. Secondary residues in animal commodities were estimated based on “maximum reasonably balanced diets” a nd transfer information from metabolism studies. Drinking water estimates were incorporated4

directly into the dietary exposure assessment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water.

i. Food. Acu te Exposure. Mesotrione is not considered to be acutely toxic and an acute toxicological endpoint was not selected by the Agency.

Chronic Exposure. The mesotrione chronic dietary (food only) risk assessment was performed for all population subgroups wit h a chronic reference dose of 0.007 mg/kg

bw/day based on a mouse reproduction study with a Lowest Observable Adverse Effect Level (LOAEL) of 2.1 mg/kg

- bw/day and an uncertainty factor of 300X. The 300

- fold safety factor includes intra

- and interspecies v ariations (100X) and an additional FQPA safety factor of 3X (absence of NOAEL). For the purpose of the aggregate risk assessment, exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the LOAEL by the exposu re for each population subgroup. In addition, exposure was also expressed as a percent of the reference dose (%RfD). Chronic (food only) exposure to the U.S. population resulted in a MOE of 129,636 (0.2% of the chronic RfD of 0.007 mg/kg

- bw/day). The mo st sensitive sub

population was children (1

- 2 years old) with a MOE of 49,607 (0. 6% of the chronic RfD). T he benchmark MOE for this assessment was 300

.

Cancer

. Mesotrione is considered “not likely to be a human carcinogen”. Therefore, no cancer risk a ssessment was performed for mesotrione.

ii. Drinking water

. The Estimated Drinking Water Concentrations (EDWCs) of mesotrione were determined using Tier l SCI

- GROW and PRZM

- GW which estimate pesticide concentration in ground water and Tier II PRZM/EXAMS w hich estimates pesticide concentration in surface water. Currently registered and pending (HT soybeans) plus proposed uses on citrus fruit , pome fruit, stone fruit and tree nuts were assessed. Based on the PRZM

- GW modeling, the currently registered Exper imental Use Permit (EUP) on soybeans provided a groundwater chronic EDWC of 16.6 ppb. Based on Tier II PRZM/EXAMS modeling for surface water, the soybean EUP provided a chronic EDWC of 5.1 ppb. Since the ground water EDWC exceeds the surface water EDWC, the ground water value was used for risk assessment purposes and will be considered protective for any surface water exposure concerns.

Chronic Exposure from Drinking Water

. The chronic ground water EDWC of 16.6 ppb was input directly into the DEEM

- FCI D software as “water, direct and indirect, all sources” to model the chronic drinking water exposures. Chronic drinking water exposure to the U.S. population resulted in a MOE of 6,042 (5.0% of the cRfD of 0.007 mg/kg

- bw/day). Chronic drinking water expo sure to the most exposed sub

- population (all infants, <1 year old) resulted in a MOE of 2,343 (12.8% of the cRfD of 0.007 mg/kg

bw/day). The b enchmark MOE for this assessment was 300

.

2. Non

- dietary exposure

. Currently the herbicide used on turfgrasses containing mesotrione is formulated as a liquid and marketed under the trade name TenacityTM, 0.08% Mesotrione on Fertilizer, 0.19% Mesotrione on Fertilizer, and 0.25% Mesotrione5

on Fertilizer. These products are used for selective contact and residual co ntrol of weeds in turfgrasses for golf courses and sod farms. TenacityTM is labeled for use only by professional applicators; therefore, residential handler application scenarios were not assessed. Residential (non

- occupational) risk assessments were cond ucted for potential post

- application exposure to adults and youth on treated golf courses.

The post

- application exposures on treated golf courses include dermal exposures due to contact activities with the treated areas. Risks due to short

- term exposure s (1

- 30 days) were assessed using the Margin of Exposure (MOE) approach. Based on the use pattern of mesotrione on turf, intermediate

- term exposures (1 to 6 months) are unlikely and long

term exposures (greater than six months) are not expected. Therefor e, intermediate

- term and long

- term risks were not assessed.

Residential exposures were assessed assuming a one

- time maximum application rate of 0.25 pounds of active ingredient per acre (0.25 lb a.i./A or 5.74E

- 06 lbs a.i./ft 2 ) per application of Tenacity TM, 0.19% Mesotrione on Fertilizer, and 0.25% Mesotrione on Fertilizer. Residential exposures were assessed assuming a one

- time maximum application rate of 0.15 pounds of active ingredient per acre (0.15 lb a.i./A or 3.44E

- 06 lbs a.i./ft 2 ) per application of 0.08% Mesotrione on Fertilizer. The absorbed dose was assumed to be 1% for dermal exposure. Dermal risks were assessed against a lowest observed adverse effect level (LOAEL) of 2.1 mg/kg

- bw /day fro m a mouse reproduction study.

Residential handler ri sks were calculat ed for granular application of m esotrione. The short

- term MOEs were 8,129 (Granular Open Pour Belly Grinder Loader Applicator) and 164,815 (Push Spreader Loader Applicator). Since the calculated residential hander exposures were found to be well above the EPA’s level of concern (MOEs>300), there does not appear to be an un acceptable level of risk to residential handler s resulting from applications of mesotrione products to turf.

Post

- application dermal exposure risks for adults and youth s due to physical activities on turf, mowing, a nd golfing were calculated for m esotrione using the calculated TTR value of 0.0056 μg/cm 2 . The short

- term MOEs for high contact dermal exposure resulting from activities on turf were 9,983 (adults 26

- 81 years old), and 5,084 (children 1

- 2 years old). The short

- term MOEs for mowing were 544,553 (adults 26

- 81 years old) and 474,215 (youths 11

- 16 years old). The short

- term MOEs for golfing were 141,276 (adults 26

- 81 years old), 121,248 (youths 11

- 16 years old), and 103,277 ( youths 6

- 11 years old). T he calculated post

- application exposures were found to be well above the EPA’s level of concern (MOEs > 300)

.

Post

- application dermal exposure risks for adults and youths due to physical activities on turf, mowing, and golfing were calculated for TenacityTM using the calculated TTR value of 0.083 μg/cm 2 . The short

- term MOEs for high contact dermal exposure resulting from activities on turf were 2,219 (adults 26

- 81 years old), and 1,121 (children 1

- 2 years old). The short

- term MOEs for mowing were 108,911 (adults 26

- 81 years old) and 94,843 (youths 11

- 16 years old). The short

- term MOEs for golfing were 28,255 (adults 26

- 816

years old), 24,250 (youths 11

- 16 years old), and 20,655 (youths 6

- 11 years old). T he calculate d post

- application exposures were found to be well above the EPA ’s level of concern (MOEs > 300).

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. Section 408(b)(2)(D)(v) requires that, when considering whethe r to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity”. The EPA does not have, at th is time, available data to determine whether mesotrione has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. For the purposes of this tolerance action, the EPA has not assumed that meso trione has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. The chronic dietary exposure analysis (food plus water) showed that exposu re from all registered, pending and proposed mesotrione crop uses resul t in a MOE of 5,769 (5.2% of the chronic RfD) for the general U.S. population.

2. Infants and children

. The chronic dietary exposure analysis (food plus water) showed that exposure from all registered, pending and proposed mesotrione uses would result in a MOE of 2,266 (13.2% of the chronic RfD) for infants less than one year old (the most sensitive population subgroup). A short

- term aggregate MOE of 338 (LOC = 300) was determined for ch ildren (1

- 6 years old). A ll aggregate MOEs e xceed the benchmark M OE of 300.

F. International Tolerances

There are currently no Maximum Residue Limits (MRLs) set for mesotrione for crops by the Codex Alimentarius Commission. International MRLs for the herbicide mesotrione have been established for various agricultural commodities in a number of countries including Argentina, Austria, Belgium, Brazil, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Luxembourg, Morocco, Netherlands, Serbia and Montenegro, Slovak Republic, Slovenia, South Africa, and the United States.